Abstract

Background

Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation
into oligomers and tangles is considered an important pathological event in tauopathies,
such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are
also associated with deficits in synaptic plasticity such as long-term potentiation
(LTP), but the specific role of tau in the manifestation of these deficiencies is
not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3
(BL6) mice expressing mutant tau that is identified in some inherited FTDs.

Results

We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase
(L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This
enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that
mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally,
we also found that expression of mutant tau led to severe sensorimotor-gating and
hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice.

Conclusions

We show for the first time that hippocampal GABAergic function is impaired by pathological
tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased
understanding of the molecular mechanisms underlying the synaptic failure in AD and
FTD is critical to identifying targets for therapies to restore cognitive deficiencies
associated with tauopathies.